TRPV1 activation in human Langerhans cells and T cells inhibits mucosal HIV-1 infection via CGRP-dependent and independent mechanisms.

Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4+ T cells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4+ T cells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4+ T cells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC-T cell conjugate formation and consequently T cell infection. Our results reveal that TRPV1 activation in human LCs and CD4+ T cells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.

Impact of body mass index on the oncological outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate the association between body mass index (BMI) and oncological outcomes in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively reviewed 237 consecutive patients treated with RNU for UTUC at our institution between 1990 and 2012. Univariable and multivariable cox regression models investigated the association of BMI with disease recurrence, cancer-specific mortality, and overall mortality. RESULTS: From the 237 patients, 104 (44%) had a BMI < 25 kg/m2, 88 (37%) had a BMI between 25 and 29.9 kg/m2, and 45 (19%) had a BMI ≥ 30 kg/m2 at the time of surgery. Within a median follow-up of 44 months (IQR: 24-79), 53 patients (22.4%) experienced a disease recurrence, 85 patients (35.9%) had bladder recurrence, and 44 patients (18.6%) died from the disease. The 5 year recurrence-free and cancer-specific survival rates were, respectively, 32 and 56% for BMI ≥ 30 kg/m2, 45 and 74% for patients with BMI 25-29.9 kg/m2, and 69 and 81% for patients with BMI < 25 kg/m2. In multivariable analyses that adjusted for the effects of the standard clinico-pathological features, BMI ≥ 30 kg/m2 was associated with a higher risk of disease recurrence (HR 3.23; 95% CI 2.3-6.6, p < 0.001) and cancer-specific mortality (HR 3.84; 95% CI 2.8-6.5; p < 0.001). CONCLUSIONS: Obesity was independently associated with higher risks of disease recurrence and cancer-specific mortality in patients treated with RNU for UTUC.

Impact of body mass index on the oncological outcomes of patients treated with radical cystectomy for muscle-invasive bladder cancer.

PURPOSE: Body mass index (BMI) has been associated with worse outcomes in several solid malignancies. We aimed to evaluate the association between BMI and oncological outcomes in patients treated with radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB). METHODS: We retrospectively reviewed 701 consecutive patients treated with RC and pelvic lymphadenectomy for UCB at our institution between 1995 and 2011. Univariable and multivariable Cox regression models investigated the association of BMI with disease recurrence and cancer-specific mortality. BMI was analyzed as both continuous and categorical variable (<25 vs. 25-29 vs. ≥30 kg/m2). RESULTS: From the 701 patients, 275 (39.2 %) had a BMI < 25 kg/m2, 280 (39.9 %) had a BMI between 25 and 29.9 kg/m2, and 146 (20.9 %) had a BMI â©¾ 30 kg/m2. Within a median follow-up of 45 months (IQR 23-75), 163 patients (23.3 %) experienced a disease recurrence and 127 (18.1 %) died from the disease. In univariable analyses, BMI â©¾ 30 kg/m2 was associated with a higher risk of disease recurrence and cancer-specific mortality (both p values <0.01). In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI â©¾ 30 kg/m2 was associated with both higher risks of disease recurrence (HR 1.58; 95 % CI 1.06-2.34, p = 0.02) and cancer-specific mortality (HR 1.58; 95 % CI 1.01-2.48; p = 0.04). CONCLUSIONS: Obesity was independently associated with higher risks of disease recurrence and cancer-specific mortality in patients treated with RC for muscle-invasive UCB. BMI is a modifiable feature that may have significant individual and public health implications in patients with muscle-invasive UCB.

Gleason Score Determination with Transrectal Ultrasound-Magnetic Resonance Imaging Fusion Guided Prostate Biopsies--Are We Gaining in Accuracy?

PURPOSE: We evaluated the accuracy of prostate magnetic resonance imaging- transrectal ultrasound targeted biopsy for Gleason score determination. MATERIALS AND METHODS: We selected 125 consecutive patients treated with radical prostatectomy for a clinically localized prostate cancer diagnosed on magnetic resonance imaging-transrectal ultrasound targeted biopsy and/or systematic biopsy. On multiparametric magnetic resonance imaging each suspicious area was graded according to PI-RADS™ score. A correlation analysis between multiparametric magnetic resonance imaging and pathological findings was performed. Factors associated with determining the accuracy of Gleason score on targeted biopsy were statistically assessed. RESULTS: Pathological analysis of radical prostatectomy specimens detected 230 tumor foci. Multiparametric magnetic resonance imaging detected 151 suspicious areas. Of these areas targeted biopsy showed 126 cancer foci in 115 patients, and detected the index lesion in all of them. The primary Gleason grade, secondary Gleason grade and Gleason score of the 126 individual tumors were determined accurately in 114 (90%), 75 (59%) and 85 (67%) cases, respectively. Maximal Gleason score was determined accurately in 80 (70%) patients. Gleason score determination accuracy on targeted biopsy was significantly higher for low Gleason and high PI-RADS score tumors. CONCLUSIONS: Magnetic resonance imaging-transrectal ultrasound targeted biopsy allowed for an accurate estimation of Gleason score in more than two-thirds of patients. Gleason score misclassification was mostly due to a lack of accuracy in the determination of the secondary Gleason grade.

Prostate cancer incidence on cystoprostatectomy specimens is directly linked to age: results from a multicentre study.

OBJECTIVE: To assess the incidence and age-related histopathological characteristics of incidentally diagnosed prostate cancer from specimens obtained via radical cystoprostatectomy (RCP) for muscle-invasive bladder cancer. PATIENTS AND METHODS: A retrospective review of the histopathological features of 2424 male patients who underwent a RCP for bladder cancer was done at eight centres between January 1996 and June 2012. No patient had preoperative suspicion of prostate cancer. Statistical analyses were performed in different age-related groups. RESULTS: Overall, prostate cancer was diagnosed in 518 men (21.4%). Incidences varied significantly according to age (5.2% in those aged <50 years to 30.5% in those aged >75 years, P < 0.001). Most of the prostate cancers were considered as 'non-aggressive', that is to say organ-confined (≤pT2) and well-differentiated (Gleason score <7). Tumour-Node-Metastasis (TNM) stage and proportion with a Gleason score of ≥7 were significantly greater in older patients (P < 0.001). Apart from age, there were no preoperative predictive factors for 'non-aggressive' prostate-cancer status. At the end of the follow-up, only nine patients (1.7%) had biochemical recurrence of prostate cancer, and no preoperative predictive factors were identified. CONCLUSION: The rate of incidentally diagnosed prostate cancer from RCP specimens is ≈20%, most of them being organ-confined and well-differentiated. The probability of having a 'non-aggressive' prostate cancer decreases in older men.

TMPRSS2-ERG fusion transcripts expression in patients referred for prostate biopsy: combining detection in urine and needle rinse material.

OBJECTIVES: The objective of this study was to combine urine and prostate biopsy rinse material (BRM) assays to increase sensitivity for fusion gene detection. PATIENTS AND METHODS: A total of 194 patients with suspicion of prostate cancer were prospectively included. Urine samples were collected before or after prostate biopsy, as well as BRM. RT-qPCR was used for the detection of fusion transcripts. A microfocal cancer on biopsy was defined by a single core involved with less than 3 mm of Gleason score 3 + 3 cancer. The association between RT-qPCR and biopsy results was statistically assessed. RESULTS: Seven patients were excluded because of insufficient material. Cancer was detected on biopsy in 100 (53%) patients. Urine alone, BRM alone and both samples were obtained in 155, 164 and 132 patients, respectively. In patients with evidence of cancer on biopsy, a fusion transcript was detected in 63, 55 and 73% of the cases on urine alone, BRM alone and paired samples, respectively. Fusion gene detection on BRM was only associated with the amount of cancer on biopsy. Urine fusion score had a larger area under the curve than serum PSA (p = 0.002) and was significantly higher in patients with high Gleason score and significant cancer on biopsy. Assays of paired samples allowed increasing sensitivity in all subgroups of patients. CONCLUSIONS: TMPRSS2-ERG fusion gene detection may be performed both in the urine and BRM to increase sensitivity. However, only T-E urine score was associated with adverse pathological features.

Oncological outcomes of advanced muscle-invasive bladder cancer with a micropapillary variant after radical cystectomy and adjuvant platinum-based chemotherapy.

OBJECTIVE: To assess the oncological outcomes of radical cystectomy (RC) and adjuvant chemotherapy to treat muscle-invasive bladder cancer (MIBC) with a micropapillary component (MPC), and to compare outcomes with those from pure urothelial carcinoma (PUC). MATERIALS AND METHODS: A retrospective review of clinicopathological and follow-up data was performed for all patients treated by RC and adjuvant platinum-based chemotherapy for advanced MIBC in three tertiary reference centers between 1999 and 2012. Uni- and multivariate Cox's regression analyses evaluated the association of the presence of MPC with disease recurrence and cancer-specific mortality. RESULTS: Two hundred and thirty-five (88 %) PUC and 31 (12 %) MPC cases were included. Median age was 65 (39-83) years in the PUC group and 62 (45-80) years in the MPC group. Median survival was 29 months in the MPC versus 31 months in the PUC group. No significant difference was observed between the groups regarding main clinical and pathological characteristics. The median number of treatment cycles administered was 6 (3-8) in the PUC versus 5 (3-8) in the MPC group (p = 0.45). Five-year disease-free recurrence and cancer-specific survival (CSS) rates were 15 and 24 %, respectively, in the MPC versus 42 and 47 %, respectively, in the PUC group (p = 0.007 and 0.058). In multivariate analyses, ASA score, soft tissue surgical margins, and MPC were associated with disease recurrence (p = 0.022, 0.001, and 0.015, respectively). We found no association between MPC and cancer-specific mortality (univariate, p = 0.06). CONCLUSION: MPC was associated with higher recurrence rates after RC and platinum-based adjuvant chemotherapy than that with pure urothelial tumors.

The use of partial nephrectomy: results from a contemporary national prospective multicenter study.

PURPOSE: Despite benefits in functional renal outcome and favorable oncological efficacy, previous studies show marked underuse of partial nephrectomy (PN). We investigated national utilization of partial and radical nephrectomy (RN) using a contemporary, prospective population-based cohort. METHODS: Between June and December 2010, 1,237 patients were treated by PN or RN for renal cell carcinoma in 56 French centers. Data were prospectively collected, and statistical analyses were performed. RESULTS: Overall, 667 (53.9 %) and 570 patients (46.1 %) underwent RN and PN, respectively. In case of PN, surgical approach was an open PN in 63.3 % of cases, a laparoscopic PN in 21.0 % of cases and a robot-assisted PN in 15.7 % of cases. PN was used in T1a, T1b, T2 and T3 tumors in 395 (76.7 %), 131 (38.2 %), 29 (14.7 %) and 7 (4.6 %), respectively. Median ischemia time was 16 min [0-60], and mean blood loss was 280.4 ml (±339.9). Tumor characteristics and operative features were significantly different according to the surgical approach. Warm ischemia time was significantly higher in case of laparoscopic or robot-assisted procedure (p < 0.001). There was no statistical significant difference in blood loss and transfusion rate according to surgical approach. Postoperative medical and surgical complications occurred in 8.2 and 10.0 % of PN, respectively, with no significant difference according to surgical approach. CONCLUSIONS: Partial nephrectomy for renal cell carcinoma is commonly used in this French centers sample. Mini-invasive approaches represent also a significant part of all partial nephrectomies with no difference in terms of complication rates.

Tumor target volume for focal therapy of prostate cancer-does multiparametric magnetic resonance imaging allow for a reliable estimation?

PURPOSE: We determined whether endorectal multiparametric magnetic resonance imaging at 1.5 Tesla could predict tumor target volume in the perspective of focal therapy of prostate cancer. MATERIALS AND METHODS: A total of 84 consecutive patients underwent multiparametric magnetic resonance imaging before radical prostatectomy. The volume of each suspicious area detected on magnetic resonance imaging and of all surgical histological foci was determined by planimetry. We first used each magnetic resonance imaging sequence (T2-weighted, diffusion weighted and dynamic contrast enhanced) and then the sequence showing the largest tumor area (multiparametric volume). Finally, the largest area of any sequence was used to calculate a target volume according to the volume of a cylinder. Agreement between magnetic resonance imaging and pathological findings was assessed by linear regression and residual analysis. RESULTS: Histology revealed 99 significant tumors with a volume of greater than 0.2 cc and/or a Gleason score of greater than 6. Of the tumors 16 (16.2%) were undetected by multiparametric magnetic resonance imaging. Linear regression analysis showed that tumor volume estimated by T2-weighted or diffusion weighted imaging correlated significantly with pathological volume (r(2) = 0.82 and 0.83, respectively). Residuals from diffusion weighted imaging volume estimations did not significantly differ from 0. Nevertheless, diffusion weighted imaging underestimated pathological volume in 43 of 87 cases (49%) by a mean of 0.56 cc (range 0.005 to 2.84). Multiparametric and target volumes significantly overestimated pathological volume by a mean of 16% and 44% with underestimation in 28 (32%) and 15 cases (17%), respectively. Volume underestimation was significantly higher for tumor foci less than 0.5 cc. The percent of Gleason grade 4 did not influence tumor volume estimation. CONCLUSIONS: Magnetic resonance imaging can detect most significant tumors. However, delineating a target volume may require further adjustment before planning magnetic resonance imaging targeted focal treatment.

Association of oncofetal protein expression with clinical outcomes in patients with urothelial carcinoma of the bladder.

PURPOSE: Oncofetal proteins are expressed in the developing embryo. Oncofetal protein expression correlates with the clinical outcome of nonmuscle invasive bladder urothelial carcinoma. IMP3, MAGE-A, glypican-3 and TPBG are oncofetal proteins that have not been well characterized in urothelial carcinoma of the bladder. MATERIALS AND METHODS: We investigated the expression of these 4 proteins and their association with clinical outcomes using tissue microarrays from 384 consecutive patients treated with radical cystectomy between 1988 and 2003 at 1 academic center. We stained for IMP3, MAGE-A, glypican-3 and TPBG. Univariable and multivariable Cox regression analyses were done to evaluate the association of oncofetal protein expression with disease recurrence and cancer specific mortality. RESULTS: IMP3, MAGE-A, glypican-3 and TPBG were expressed in 39.5%, 45%, 6% and 85% of urothelial bladder carcinomas, respectively. Expression was tumor specific and did not correlate with pathological features except for TPBG. At a median followup of 128 months 176 patients (46%) experienced disease recurrence, 175 (45.5%) had died of the disease and 96 (27.5%) had died of another cause. On univariable analysis IMP3 and MAGE-A expression was associated with an increased risk of disease recurrence (p <0.001 and 0.03) and cancer specific mortality (p = 0.004 and 0.03, respectively). On multivariable Cox regression analysis adjusted for the effects of standard clinicopathological features IMP3 and MAGE-A expression was independently associated with disease recurrence (p = 0.004, HR 1.55, 95% CI 1.15-2.11 and p = 0.02, HR 1.44, 95% CI 1.05-1.99, respectively) but not with cancer specific mortality. CONCLUSIONS: Oncofetal proteins are commonly and differentially expressed in urothelial carcinoma of the bladder compared to normal urothelium. IMP3 and MAGE-A expression was associated with disease recurrence and cancer specific mortality but glypican-3 and TPBG expression was not.

Clinicopathological characteristics of incidental prostate cancer discovered from radical cystoprostatectomy specimen: a multicenter French study.

PURPOSE: The present study assessed the incidence and histopathological features of incidentally diagnosed prostate cancer (PCa) in specimens from radical cystoprostatectomy (RCP) for bladder cancer. The patient outcomes also were evaluated. METHODS: We retrospectively reviewed the histopathological features and survival data of 4,299 male patients who underwent a RCP for bladder cancer at 25 French centers between January 1996 and June 2012. No patients had preoperative clinical or biological suspicion of PCa. RESULTS: Among the 4,299 RCP specimens, PCa was diagnosed in 931 patients (21.7%). Most tumors (90.1%) were organ-confined (pT2), whereas 9.9% of them were diagnosed at a locally advanced stage (≥pT3). Gleason score was <6 in 129 cases (13.9%), 6 in 575 cases (61.7%), 7 (3 + 4) in 149 cases (16.0%), 7 (4 + 3) in 38 cases (4.1%), and >7 in 40 cases (4.3%). After a median follow-up of 25.5 months (interquartile range 14.2-47.4), 35.4% of patients had bladder cancer recurrence and 23.8% died of bladder cancer. Only 16 patients (1.9%) experienced PCa biochemical recurrence during follow-up, and no preoperative predictive factor was identified. No patients died from PCa. CONCLUSIONS: The rate of incidentally diagnosed PCa in RCP specimens was 21.7%. The majority of these PCas were organ-confined. PCa recurrence occurred in only 1.9% of cases during follow-up.

Impact of smoking status and cumulative exposure on intravesical recurrence of upper tract urothelial carcinoma after radical nephroureterectomy.

OBJECTIVE: To assess the impact of cigarette smoking status, cumulative smoking exposure, and time from cessation on intravesical recurrence (IVR) outcomes in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: In all, 519 patients underwent RNU at five institutions. Smoking history included smoking status, quantity of cigarettes smoked per day (cpd), duration, and time from cessation. The cumulative smoking exposure was categorised as light-short-term (≤19 cpd and ≤19.9 years), moderate (all combinations except light-short-term and heavy-long-term), and heavy-long-term (≥20 cpd and ≥20 years). Univariable/multivariable cox regression analyses assessed the effects of smoking on IVR. RESULTS: In all, 190 patients (36%) never smoked; 205 (40%) and 125 (24%) were former and current smokers, respectively. Among smokers, 42 (8%), 185 (36%), and 102 (20%) patients were light-short-term, moderate, and heavy-long-term smokers, respectively. Within a median follow-up of 37 months, 152 patients (29%) had IVR. Actuarial IVR-free-survival estimates (standard error) at 2, 5, and 10 years were 72 (2)%, 58 (3)%, and 51 (4)%, respectively. In multivariable analyses, current smoking status, smoking intensity (≥20 cpd), smoking duration (≥20 years), and heavy-long-term smoking were associated with higher risk of IVR (all P ≤ 0.01). Patients who quit smoking ≥10 years before RNU had better IVR outcomes than current smokers and those patients who quit smoking <10 years before RNU. CONCLUSIONS: Cigarette smoking is significantly associated with IVR in patients treated with RNU for UTUC. Current and heavy-long-term smokers have the highest risk of IVR. Smoking cessation for >10 years before RNU seems to mitigate these detrimental effects.

Hereditary-like urothelial carcinomas of the upper urinary tract benefit more from adjuvant cisplatin-based chemotherapy after radical nephroureterectomy than do sporadic tumours.

OBJECTIVE: To evaluate the impact of 'hereditary-like' status in upper tract urothelial carcinoma (UTUC) on the survival of patients who have undergone radical nephroureterectomy (RNU) and adjuvant chemotherapy. PATIENTS AND METHODS: A multicentre retrospective study was performed on all patients with high-risk UTUC who underwent RNU and adjuvant cisplatin-based chemotherapy. Using a patient risk identification tool, we distinguished tumours suspected to be hereditary from sporadic tumours and compared survival rates. RESULTS: A total of 112 patients with a median age of 67 years were included. Hereditary-like tumour status was detected in 35 patients (31.3%), while 77 patients (68.7%) had sporadic tumours. The median age was significantly younger in the hereditary-like tumour group (56.0 vs 69.8 years, P < 0.001). Overall survival (OS) after chemotherapy was significantly better in the group with hereditary-like tumours than in the group with sporadic tumours (5-year OS: 48.2 vs 32%; P = 0.008). The cancer-specific survival (CSS) rate was significantly better in the group with 'hereditary-like' tumours than in the group with sporadic tumours (5-year CSS: 58 vs 35%; P = 0.006). Although there was a trend in favour of the hereditary-like tumours, we observed no significant difference regarding progression-free survival (PFS) between the two groups (5-year PFS: 71 vs 52%; P = 0.07). CONCLUSION: Adjuvant chemotherapy after RNU improves survival outcomes in patients with hereditary-like UTUC compared with those with sporadic tumours.

Impact of micropapillary histological variant on survival after radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To assess the impact of micropapillary histological variant on oncological outcome after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinomas (UTUCs). METHODS: A French multicenter retrospective study was performed on patients who underwent RNU between 1995 and 2010. Pathological reports were reviewed to identify patients with pure urothelial carcinomas (PUC) and those with micropapillary histological variant (MPC). Uni- and multivariate Cox regression analyses were performed to identify factors predictive of survival. RESULTS: Overall, 519 patients were included and divided into two groups: 480 PUC and 39 MPC. Median follow-up were 28 and 19 months, respectively (p = 0.63). There was no difference between the two groups for gender, age and tumor location (pelvicalyceal or ureteral). MPC was associated with high-stage and high-grade UTUC (p < 0.001 and 0.04). No difference was observed between the two groups for 5-year cancer-specific survival (76.1 vs. 88.2 %; p = 0.54). The 5-year metastasis-free survival was significantly lower in the MPC group (48.9 vs. 73.8 %; p = 0.037). In multivariate analysis, pT stage, lymphovascular invasion, margin status and adjuvant chemotherapy administration were independent predictors of specific survival (p = 0.002; 0.001; 0.02; 0.01), contrary to histological variant (p = 0.94). CONCLUSIONS: Micropapillary histological variant was associated with advanced UTUC and reduced metastasis-free survival after RNU. It should be considered as an aggressive tumor and thus be stated in any pathological report after radical surgery.

Risk stratification of metastatic recurrence in invasive upper urinary tract carcinoma after radical nephroureterectomy without lymphadenectomy.

PURPOSE: To assess the risk factors of metastasis relapse in pT2-3 upper tract urothelial carcinomas (UTUCs) treated by radical nephroureterectomy (RNU) without lymphadenectomy (LN). METHODS: A multicentric retrospective study was performed for pT2-3 pNx UTUCs treated by RNU between 1995 and 2010. The following criteria were retrieved: age, gender, American Society of Anaesthesiologists physical status, surgical approach, preoperative hydronephrosis, stage, grade, tumor location, surgical margin, lymphovascular invasion (LVI) status and outcomes. Metastasis-free survival (MFS) was measured by Kaplan-Meier method with the log-rank test. RESULTS: Overall, 151 patients were included. The median follow-up was 18.5 months (IQR 9.5-37.9). The 2- and 5-year MFS were 69 % ± 4.5 and 54.1 % ± 5.8, respectively. In univariate analysis, ureteral location, pT3 stage, positive LVI status and positive surgical margin were significantly associated with worse MFS (p = 0.03; 0.02; 0.01 and 0.006, respectively). In the multivariate analysis of ureteral location and pT3 stage were independent prognostic factors (p = 0.03 and 0.03, respectively). Based on the results of the univariate analysis, we proposed a risk model predicting MFS, which classifies patients into 3 categories with different overall survival (p < 0.001). CONCLUSION: In view of our data, tumor location, T stage, LVI and surgical margin status are mandatory to predict survival in case of RN without LN. Contingent upon external validation, our risk model based on these variables could be useful to provide relevant information concerning metastasis relapse probability and necessity of close follow-up for these patients.

Quality of life of 1276 elderly patients with prostate cancer, starting treatment with a gonadotropin-releasing hormone agonist: results of a French observational study.

This French observational, longitudinal, prospective study described the health-related quality of life (HRQoL) of elderly men (≥75 years old) with prostate cancer after initiating gonadotropin-releasing hormone (GnRH) agonist therapy. At baseline and 3-6 months after baseline, European Organisation for Research and Treatment of Cancer quality of life questionnaire-core 30 (QLQ-C30) and prostate-specific (QLQ-PR25) questionnaires were completed by patients. Data from 1276 patients were analyzed. At baseline, mean (±SD) age was 80 (±4.1) years, 29.1% of patients had Gleason scores ≥8 and 24.9% had metastases. At baseline, increasing age, presence of metastasis and presence of comorbidity had a negative impact on QLQ-C30 and QLQ-PR25 scores. At follow-up, improvement in emotional-functioning (2.8; p < 0.001), social-functioning (1.7; p = 0.011), global HRQoL (1.6; p = 0.029), sleep-disturbance (-2.1; p = 0.011), appetite-loss (-4.0; p < 0.001) and pain (-4.1; p < 0.001) QLQ-C30 scores were observed. In addition, there was a worsening in treatment-related symptom (8.6; p < 0.001), sexual-activity (-5.5; p < 0.001) and sexual-functioning (-22.6; p < 0.001) QLQ-PR25 scores, and an improvement in urinary symptoms (-3.7; p < 0.001) and incontinence aid (-2.9; p = 0.023) QLQ-PR25 scores. This study shows that, apart from the expected impact on sexual functioning domains, HRQoL is not adversely affected by 3-6 months of GnRH agonist therapy in older men with prostate cancer.

Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib.

UNLABELLED: There is growing evidence that sunitinib plasma levels have an impact on treatment outcome in patients with metastatic renal cell carcinoma (mRCC). We studied the impact of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics, and additionally, sunitinib pharmacodynamics on dose reductions of the tyrosine kinase inhibitor. METHODS: We retrospectively analyzed germ-line DNA retrieved from mRCC patients receiving sunitinib as first-line therapy. We genotyped 11 key SNPs, respectively, in ABCB1, NR1/2, NR1/3 and CYP3A5, involved in sunitinib pharmacokinetics as well as VEGFR1 and VEGFR3, which have been suggested as regulators of sunitinib pharmacodynamics. Association between these SNPs and time-to-dose-reduction (TTDR) was studied by Cox regression. RESULTS: We identified 96 patients who were treated with sunitinib and from whom germ-line DNA and data on dose reductions were available. We observed an increased TTDR in patients carrying the TT-genotype in ABCB1 rs1125803 compared to patients with CC- or CT-genotypes (19 vs. 7 cycles; p = 0.031 on univariate analysis and p = 0.012 on multivariate analysis) and an increased TTDR in patients carrying the TT/TA-variant in ABCB1 rs2032582 compared to patients with the GG- or GT/GA-variant (19 vs. 7 cycles; p = 0.046 on univariate analysis and p = 0.024 on multivariate analysis). CONCLUSION: mRCC patients carrying the rs1128503 TT-variant or the TT/TA-variant in rs2032582 in ABCB1, which encodes for an efflux pump, do require less dose reductions due to adverse events compared to patients with the wild type or heterozygote variants in these genes.

microRNA expression profile in a large series of bladder tumors: identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer.

The aim of this study was to evaluate the expression levels of microRNAs (miRNAs) in bladder tumors in order to identify miRNAs involved in bladder carcinogenesis with potential prognostic implications. Expression levels of miRNAs were assessed by quantitative real-time RT-PCR in 11 human normal bladder and 166 bladder tumor samples (86 non-muscle-invasive bladder cancer (NMIBC) and 80 muscle-invasive bladder cancer (MIBC)). The expression level of 804 miRNAs was initially measured in a well-defined series of seven NMIBC, MIBC and normal bladder samples (screening set). The most strongly deregulated miRNAs in tumor samples compared to normal bladder tissue were then selected for RT-PCR validation in a well-characterized independent series of 152 bladder tumors (validation set), and in six bladder cancer cell lines. Expression levels of these miRNAs were tested for their association with clinical outcome. A robust group of 15 miRNAs was found to be significantly deregulated in bladder cancer. Except for two miRNAs, miR-146b and miR-9, which were specifically upregulated in MIBC, the majority of miRNAs (n = 13) were deregulated in the same way in the two types of bladder tumors, irrespective of pathological stage : three miRNAs were upregulated (miR-200b, miR-182 and miR-138) and the other 10 miRNAs were downregulated (miR-1, miR-133a, miR-133b, miR-145, miR-143, miR-204, miR-921, miR-1281, miR-199a and miR-199b). A 3-miRNA signature (miR-9, miR-182 and miR-200b) was found to be related to MIBC tumor aggressiveness and was associated with both recurrence-free and overall survival in univariate analysis with a trend to significance in the multivariate analysis (p = 0.05). Our results suggested a promising individual prognostic value of these new markers.

HIV-1 efficient entry in inner foreskin is mediated by elevated CCL5/RANTES that recruits T cells and fuels conjugate formation with Langerhans cells.

Male circumcision reduces acquisition of HIV-1 by 60%. Hence, the foreskin is an HIV-1 entry portal during sexual transmission. We recently reported that efficient HIV-1 transmission occurs following 1 h of polarized exposure of the inner, but not outer, foreskin to HIV-1-infected cells, but not to cell-free virus. At this early time point, Langerhans cells (LCs) and T-cells within the inner foreskin epidermis are the first cells targeted by the virus. To gain in-depth insight into the molecular mechanisms governing inner foreskin HIV-1 entry, foreskin explants were inoculated with HIV-1-infeceted cells for 4 h. The chemokine/cytokine milieu secreted by the foreskin tissue, and resulting modifications in density and spatial distribution of T-cells and LCs, were then investigated. Our studies show that in the inner foreskin, inoculation with HIV-1-infected cells induces increased CCL5/RANTES (1.63-fold) and decreased CCL20/MIP-3-alpha (0.62-fold) secretion. Elevated CCL5/RANTES mediates recruitment of T-cells from the dermis into the epidermis, which is blocked by a neutralizing CCL5/RANTES Ab. In parallel, HIV-1-infected cells mediate a bi-phasic modification in the spatial distribution of epidermal LCs: attraction to the apical surface at 1 h, followed by migration back towards the basement membrane later on at 4 h, in correlation with reduced CCL20/MIP-3-alpha at this time point. T-cell recruitment fuels the continuous formation of LC-T-cell conjugates, permitting the transfer of HIV-1 captured by LCs. Together, these results reveal that HIV-1 induces a dynamic process of immune cells relocation in the inner foreskin that is associated with specific chemokines secretion, which favors efficient HIV-1 entry at this site.

TMPRSS2-ERG fusion transcripts in matched urine and needle rinse material after biopsy for the detection of prostate cancer.

BACKGROUND: Current methods for detecting TMPRSS2-ERG fusion transcript in the urine of patients with suspected prostate cancer lack diagnostic sensitivity. We combined urine and prostate biopsy rinse material (BRM) assays to improve the fusion gene detection rate. METHODS: Eighty patients with clinical and/or prostate-specific antigen suspicion of prostate cancer were prospectively included in the study. Urine samples were collected before and after prostate biopsy, and BRM was collected from the biopsy needle. We used reverse-transcription PCR (RT-PCR) for the detection of fusion transcripts. Microfocal cancer (MFC) on biopsy was defined by a single core involved with ≤3 mm of cancer with Gleason score 3 + 3. We statistically assessed the association between RT-PCR and biopsy results. RESULTS: Urine alone, BRM alone, and both samples were obtained in 4, 19, and 57 patients, respectively. Three patients were excluded because of insufficient material. In the remaining 77 patients, cancer was detected on biopsy in 42 (55%). The diagnostic sensitivity of the assay for cancer detection was 62% (95% CI 47%-78%), 69% (53%-85%), and 89% (73%-99%) with BRM alone, urine alone, and paired samples, respectively. The lowest values were obtained with the urine assay in patients with MFC or Gleason score >3 + 3 cancer. Assays of paired samples provided increased diagnostic sensitivity in all subgroups of patients. CONCLUSIONS: TMPRSS2-ERG fusion gene detection may be improved by performing assays in both urine and BRM. Insufficient cell numbers in urine samples and cell lysis during centrifugation may explain the low diagnostic sensitivity of the urine assay.